PROJECT SUMMARY Following stroke, numerous impairments develop that affect walking ability. We lack a clear understanding of what characterizes these impairments and their relation to impaired walking ability. For example, we applied exoskeletal knee flexion to assist those with reduced knee flexion post-stroke. The assistance improved knee flexion but surprisingly worsened compensatory motions such as hip abduction. Preliminary analysis indicated that the assistance elicited hyperexcitable quadriceps reflex activity. Additionally, the quadriceps response was abnormally coordinated with hip abductor muscles only in post-stroke individuals. These results question traditional beliefs regarding which motions are compensatory and which are due to neural impairment. Thus, the critical gap to restoring functional gait post-stroke is characterizing the interconnection between biomechanical issues and neural impairments. Our novel approach is to combine state-of-the-art methods in biomechanics and neurophysiology to develop cause-and-effect models of the interconnection between gait kinematics, hyperexcitable reflex activity and abnormal coordination. The clinical significance is the groundwork for targeted interventions such as reflex modulation and neurally intelligent exoskeletons that interact with the impaired spinal circuitry. It will be shown in our preliminary work that we have years of experience characterizing post-stroke gait impairments using reflex stimulation, robotics and computational methods that uniquely qualify our group for this project. The objective of this proposal is to establish the biomechanical and neurophysiological mechanisms underlying pathological gait post-stroke. In Aim 1, we determine whether hip abduction is a compensation for reduced knee flexion by comparing people with stroke to induced similar walking patterns in healthy individuals. Muscle activation patterns and intralimb coordination will provide evidence towards fundamental differences in neural control after stroke. In Aim 2, we use reflex neurophysiological methods to probe post- stroke individuals? reflex coordination patterns. We expect to find that hyperactive quadriceps reflexes are associated with impaired knee flexion. We additionally expect to show the interrelation between reflex activity in the quadriceps and the abductors as predicted by our models representing abnormal coordination. In Aim 3, we use reflex conditioning protocols during gait based on sophisticated paired peripheral nerve stimulation techniques. These methods will provide evidence of the spinal mechanisms at the root of abnormal reflex behavior that likely underlie impaired gait post-stroke. Together this comprehensive testing procedure incorporates biomechanics and neurophysiology to reveal new knowledge of post-stroke gait impairment. These results will have broad impact on our understanding of neuromuscular impairments and enable the development of targeted therapies for treatment.